Mitrochondrial dysfunction can result in a host of debilitating mitochondrial diseases or disorders characterized by poor growth, loss of muscle coordination, muscle weakness, visual problems, hearing problems, learning disabilities, heart disease, liver disease, kidney disease, gastrointestinal disorders, respiratory disorders, neurological problems, autonomic dysfunction, and/or dementia. In many instances, these mitochondrial diseases are caused by acquired or inherited mutations in mitochondrial DNA or in nuclear genes that code for mitochondrial components or for cellular components that act as quality control checkpoints of mitochondrial function. For example, the mitochondrial disease Parkinson's disease (PD) is a common neurodegenerative movement disorder affecting 1% of the population above the age of 60 that has be linked to acquired or spontaneous mutations in mitochondrial genes or nuclear genes relevant to mitochondrial function. PD is characterized by the preferential loss and degeneration of dopaminergic neurons of the substantia nigra (SN) pars compacta and formation of Lewy bodies. PD patients exhibit resting tremor, bradykinesia, muscle rigidity and postural instability.
Although research is ongoing, treatment options are currently limited; vitamins are frequently prescribed, though the evidence for their effectiveness is limited. Rescuing dysfunctional mitochondria provides one approach for treating mitochondrial diseases or disorders. Membrane penetrating antioxidants and pyruvate are two examples of treatment options for improving mitochondrial dysfunction. As such, there is a need for the development of new therapeutic agents and methods for the treatment of mitochondrial disease.
Neurons produced by the transdifferentiation of pluripotent stem cells or non-neuronal somatic cells may be useful for the development of therapeutics, for experimental evaluation, for transplantation, as a source of lineage- and cell-specific products, and the like, to treat human disorders, for example neurodegenerative disorders such as Parkinson's Disease. Somatic cells generated from induced pluripotent stem cells, however, can undergo cell proliferation that can, in turn, cause new genomic alterations. Methods of somatic cell to somatic cell transdifferentiation often involve an intermediate step of de-differentiation to a pluripotent cell stage before further differentiation to the somatic cell type of interest. Such reprogramming steps can be slow and inefficient, requiring significant time and manipulation in vivo. Accordingly, there is a need for a method to transdifferentiate a non-neuronal cell directly to post-mitotic neuron.